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Hypertension: how low to go? |
Summary
As blood pressure rises the risk of dying of cardiovascular disease increases. Lowering blood pressure aims to reduce the risk, but it is not certain that a low target for blood pressure will improve survival. An important consideration is the presence of other risk factors such as diabetes. Reducing the diastolic blood pressure, of a patient with hypertension but no other risk factors, to below 90 mmHg may cause more harm than benefit.
Key words: blood pressure, antihypertensives, cardiovascular disease
(Aust Prescr 2003;26:53-5)
Introduction
Epidemiological studies have established that systolic and diastolic bloodpressures have a strong, continuous, graded and aetiologically significantpositive association with cardiovascular disease outcomes. Treatment of hypertensionreduces cardiovascular risk, and this has been a major focus of campaigns aimedat reducing cardiovascular mortality and morbidity.1
We now have many effective treatments for hypertension. In recent studiesthe questions about treatment have generally addressed the refinement and comparisonof treatment regimens. The questions of which type of drug should be first-linetreatment, which type of drug is best for what type of patients, and what shouldbe the target blood pressure have all been considered.
A number of international guidelines (WHO/ISH, JNC-VI) suggest that bloodpressure should be reduced at least to below 160/90 mmHg to normalise cardiovascularrisk in patients with hypertension. In patients at higher baseline risk ofcardiovascular disease, for example those with diabetes2,the recommendations in JNC-VI are that the target blood pressure should besubstantially lower: 130/85 mmHg. This recommendation is based on the viewthat the absolute risk of a cardiovascular event in these patients is muchgreater, and therefore the absolute benefit of treatment is larger. The questionis, how good is the evidence for these recommendations?
Research evidence
Several randomised controlled trials published in the last 3-4 years are usedto support proposals for lower target blood pressures in hypertension.3,4 Inaddition, there are two cohort studies that provide important information aboutthe likely risk of heart disease in patients with blood pressures that arelower than those previously considered to be a problem.5,6
One analysis examined the outcomes for participants in the Framingham studyaccording to their baseline blood pressure.6 Ithad a particular focus on the group who started the study with a 'high-normal'blood pressure (defined as systolic pressures of 130-139 mmHg and/or diastolicpressures of 85-89 mmHg). This group did not have cardiovascular disease atthe outset of the study, but they were older, had a higher body mass indexand higher cholesterol concentrations than completely normotensive participants.After 10 years, the cumulative age-adjusted incidence of cardiovascular diseasein people with 'high-normal' blood pressure was 4.4% (95% CI* 3.2-5.5%)in women and 10.1% (95% CI 8.1-12.1%) in men, compared with 1.9% (95% CI 1.1-2.7%)and 5.8% (95% CI 4.2-7.4%) in the participants with optimal blood pressure.The 'high-normal' blood pressure appeared to be associated with an increasedrisk of cardiovascular disease, even after adjustment for other coexistingrisk factors.
An analysis of blood pressure in six different populations (USA, northernEurope, Mediterranean southern Europe, inland southern Europe, Serbia and Japan)examined the relationship between deaths from coronary heart disease and bloodpressure.5 After25 years of follow-up, for an increase of 5 mmHg in diastolic blood pressurethe relative risk of mortality ranged from1.06 (in inland southern Europe) to 1.19 (in Mediterranean southern Europe).The differences in these risks between populations for a given level of changein blood pressure were not statistically significant - that is, the relativerisk of death remained constant. The absolute riskof death, however, was clearly different among the six populations, varyingfrom 44 per 10 000 person years (Japan) to 153 per 10 000 person years (northernEurope).
These two cohort studies suggest that elevated blood pressure - accordingto whatever definition - alone does not predict risk of the final event (death)and that not all populations are equal. Although the risk goes up with increasingblood pressure very consistently, the studies do not tell us if the risk comesdown with decreasing blood pressure.
HOT study
Only one intervention study has examined the effect of lowering blood pressureto different targets in patients with or without the other major cardiovascularrisk factor of diabetes. The Hypertension Optimal Treatment (HOT) study randomised18 790 patients aged 50-80 years from 26 countries to one of three groups,each defined by a target diastolic blood pressure. The targets were < 90mmHg, < 85 mmHg and < 80 mmHg.
These targets were to be achieved by treatment with a series of drugs startingwith long-acting felodipine 5 mg per day, followed if necessary by stepwiseaddition of ACE inhibitors or beta blockers, increasing doses of felodipine,and then finally addition of a diuretic. All patients were also randomisedto receive low-dose aspirin (75 mg per day) or placebo. Follow-up was for upto five years (mean actual follow-up 3.8 years), and the main end-points werecardiovascular events, cardiovascular mortality and total mortality.
The patients in each group were similar in terms of the presence of otherrisk factors. At the start of the study 8% of patients had diabetes, and approximately15% were smokers. By the end of the study, approximately 80% of the patientswere still taking felodipine, usually with an ACE inhibitor (41%) or a betablocker (28%). The reason why 20% had stopped felodipine by the end of thestudy is not stated in the main report of the study.4
The key results of the study are summarised in Table 1.The majority of patients achieved their target blood pressure and the authorsconcluded that the intensive lowering of blood pressure in patients with hypertensionwas associated with a low rate of cardiovascular events and that the studyshowed the benefits of lowering the diastolic blood pressure down to 82.6 mmHg.The implication was therefore that targets for the treatment of hypertensionshould be lower, than the previously accepted 90 mmHg, to maximise the reductionin cardiovascular risk. This was the recommendation in much of the correspondencewhich followed the publication of the study, but is this recommendation reasonable?
Questions about the HOT study
In the lengthy correspondence about the HOT study, it was pointed out that:
– using an intention to treat analysis, there was no difference in resultsbetween treatment groups7
– the method of blood pressure measurement was not optimal8
– the data, excluding patients with diabetes, suggested an increase inmortality with lower blood pressures9
– the results did not take into account the potential increase in adverseeffects and costs of medications that might be required to achieve lower bloodpressures.10
This list of problems is not comprehensive. There was also debate about thepotential influence of the pharmaceutical company sponsoring the trial andthe promotion of calcium channel blockers as first-line treatment.
On reviewing the data in the original publication, the argument that thereis no significant difference in the results for mortality or cardiovascularevents between treatment groups (arguably the primary analysis for the primaryoutcomes) appears to be correct. The confidence intervals for the relativerisks for the comparisons between groups all include 1.00 (seethe last column in Table 1). The data for cardiovascular event rates actuallyappear to show an increase in mortality with lower blood pressure, althoughgiven the relatively small total number of deaths (approximately 600 out ofnearly 19 000 patients), the increase is not statistically significant.
There have been several subsequent analyses of the data from the HOT study.11,12 Themost comprehensive analysis examined the data set using a 'risk stratification'approach. Patients were grouped according to the presence or absence of othercardiovascular risk factors, and the frequency of events in each risk groupwas considered. The analysis suggested that the higher the risk group, themore likely the chance of cardiovascular events. Unfortunately, the analysisdid not compare the outcomes in the risk strata according to the blood pressuretarget - hence it is not helpful in assessing the value of intensive treatment.A second analysis examined the impact of the presence of other risk factorson the outcomes and concluded that blood pressure alone did not predict therisk of cardiovascular events.
Conclusion
The HOT study does not provide sufficient evidence of the benefits of intensivetreatment of blood pressure (that is, reducing diastolic pressures below 90mmHg) in patients with hypertension. However, in the original sub-group analysisof the HOT study, which looked at the results in patients with diabetes, there are differencesin the outcomes between treatment groups. Patients with diabetes in the lowesttarget blood pressure group had significantly lower rates of cardiovascularevents. Total mortality was also decreased.
This difference in the results, depending on the presence of other risk factors,highlights the need to consider hypertension in the context of the other riskfactors that an individual patient possesses. It is not sufficient to assessand manage blood pressure alone and indeed, we may be doing our patients adisservice if we do so. As with all treatment decisions, the question of overallbenefits and harms (including the cost of medication and medical care, andthe impact of taking the treatment on quality of life) need to be discussedwith the patient. Just lowering blood pressure to an arbitrary target - particularlyin a low-risk patient - may not provide benefits and may cause harm.
In patients with multiple risk factors for cardiovascular disease, for examplediabetes, we need to be more aggressive in our approach. Trials in high-riskpatients support the argument for more aggressive interventions to reduce therisk of adverse cardiovascular outcomes.3 Onesize rarely fits all - and a single target blood pressure for the treatmentof hypertension across all patient groups is clearly not justified.
E-mail: hillsu@mail.newcastle.edu.au
References
1. MacMahon S. Antihypertensive drug treatment: the potential,expected and observed effects on vascular disease. J Hypertens 1990;8 (Suppl7):S239-44.
2. Tight blood pressure control and risk of macrovascularand microvascular complications in type 2 diabetes: UKPDS 38. UK ProspectiveDiabetes Study Group [published erratum appears in Br Med J 1999;318:29]. BrMed J 1998;317:703-13.
3. PROGRESS Collaborative Group. Randomised trial of aperindopril-based blood-pressure-lowering regimen among 6105 individuals withprevious stroke or transient ischaemic attack. Lancet 2001;358:1033-41.
4. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, ElmfeldtD, Julius S, et al. Effects of intensive blood-pressure lowering and low-doseaspirin in patients with hypertension: principal results of the HypertensionOptimal Treatment (HOT) randomised trial. Lancet 1998;351:1755-62.
5. Van den Hoogen PC, Feskens EJ, Nagelkerke NJ, MenottiA, Nissinen A, Kromhout D. The relation between blood pressure and mortalitydue to coronary heart disease among men in different parts of the world. NEngl J Med 2000;342:1-8.
6. Vasan RS, Larson MG, Leip EP, Evans JC, O'Donnell CJ,Kannel WB, et al. Impact of high-normal blood pressure on the risk of cardiovasculardisease. N Engl J Med 2001;345:1291-7.
7. Avanzini F, Marchioli R, Alli C, Tognoni G. HypertensionOptimal Treatment (HOT) trial [letter]. Lancet 1998;352:571-2.
8. Simon A, Levenson J. Hypertension Optimal Treatment(HOT) trial [letter]. Lancet 1998;352:571.
9. Grossman E, Goldbourt U. Hypertension Optimal Treatment(HOT) trial [letter]. Lancet 1998;352:572.
10. Gueyffier F, Boissel JP. Hypertension Optimal Treatment(HOT) trial [letter]. Lancet 1998;352:572-3.
11. Zanchetti A, Hansson L, Menard J, Leonetti G, RahnKH, Warnold I, et al. Risk assessment and treatment benefit in intensivelytreated hypertensive patients of the Hypertension Optimal Treatment (HOT) study.J Hypertens 2001;19:819-25.
12. Zanchetti A, Hansson L, Dahlof B, Elmfeldt D, KjeldsenS, Kolloch R, et al. Effects of individual risk factors on the incidence ofcardiovascular events in the treated hypertensive patients of the HypertensionOptimal Treatment Study. J Hypertens 2001;19:1149-59.
Conflict of interest: none declared
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